Prescription Required
Manufacturer
TEVA USA
SKU
00093681773

budesonide 1 mg/2 ml inh susp (generic pulmicort)

Generic
Out of Stock

Uses

Budesonide is used orally for the management of mild to moderate Crohn's disease. Budesonide is used by oral inhalation for the management of bronchial asthma. Budesonide in fixed combination with formoterol fumarate is used by oral inhalation for the treatment of asthma and also for maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Crohn's Disease

Budesonide is used orally as delayed-release capsules for the management of mildly to moderately active Crohn's disease involving the ileum and/or ascending colon and for maintenance of clinical remission for up to 3 months in this condition.

Safety and efficacy of delayed-release budesonide capsules in the management of active Crohn's disease were evaluated in 5 randomized, double-blind (2 placebo-controlled and 3 comparative) studies that included 994 adults (17-85 years of age [mean age: 35 years]; 40% male; 97% white) with mild to moderately active Crohn's disease involving the ileum and/or the ascending colon. For clinical assessment, the Crohn's Disease Activity Index (CDAI) was used. The CDAI score is based on subjective observations by the patient (e.g., the daily number of liquid or very soft stools, severity of abdominal pain, general well-being) and objective evidence (e.g., number of extraintestinal manifestations, presence of an abdominal mass, use or nonuse of antidiarrheal drugs, the hematocrit, body weight). Clinical improvement, defined as a CDAI score of 150 or less, assessed after 8 weeks of treatment, was the primary efficacy parameter in these studies. In the 2 placebo-controlled studies, patients were randomized to receive placebo or budesonide dosages of 3, 9, or 15 mg daily. In one of these studies (patients having a median CDAI score of 290), a statistically significant difference in clinical improvement was observed in patients receiving 9-mg (4.5 mg twice daily) daily dosages of budesonide (as the delayed-release capsules) when compared with those receiving placebo (51% for budesonide versus 20% for placebo). Improvements in the quality of life, as measured by the patients' responses to the inflammatory bowel disease questionnaire, highly correlated with CDAI scores. In this study, no additional benefit in the management of active Crohn's disease was observed when budesonide dosages were increased to 15 mg daily (7.5 mg twice daily). Clinical improvement was similar in patients receiving 3-mg (1.5 mg twice daily) daily dosages of budesonide to those receiving placebo. In the other placebo-controlled study (patients having a median CDAI score of 263), no statistically significant difference in clinical improvement was observed in patients receiving 9-mg (9 mg once daily or 4.5 mg twice daily) daily dosages of budesonide delayed-release capsules when compared with those receiving placebo (48-53% for budesonide versus 33% for placebo).

Results of a comparator-drug (budesonide versus mesalamine) controlled study (patients having a median CDAI score of 272) indicate that clinical improvement was substantially higher in adults receiving 9-mg daily dosages of budesonide delayed-release capsules than in those receiving 2-g twice daily dosages of mesalamine delayed-release tablets (69% for budesonide versus 45% for mesalamine). In addition to a higher clinical improvement rate, quality-of-life scores (e.g., anxiety, depressed mood, sense of well-being, self-control, general health, vitality) were improved to a greater extent in patients receiving budesonide than in those receiving mesalamine. Similar or lower clinical improvement rates were observed (although the difference was not statistically significant) in 2 comparative clinical trials (patients having a median CDAI score of 277) when oral budesonide delayed-release capsules were compared with oral prednisolone (40 mg daily initially and then tapered). In one 12-week study, clinical improvement was observed in 42-60% of patients receiving budesonide (42% in patients receiving 4.5 mg twice daily and 60% in those receiving 9 mg once daily for 8 weeks; dosage was tapered thereafter) compared with 60% of those receiving prednisolone (40 mg daily for 2 weeks and tapered thereafter). In the second trial (10 weeks' duration), clinical improvement was observed in 52 or 65% of patients receiving budesonide (9 mg daily for 8 weeks followed by 6 mg daily for 2 weeks) or prednisolone (40 mg daily for 2 weeks, 30 mg for 2 weeks, 25 mg for 2 weeks; daily dosage was then decreased by 5 mg each week for the last 4 weeks), respectively.

Results of a pooled analysis of randomized clinical trials have shown that adults with an active episode of mildly to moderately active Crohn's disease receiving budesonide are 82 or 73% more likely to achieve remission than those receiving placebo (relative risk of 1.82) or mesalamine (relative risk of 1.73), respectively. In addition, results of the pooled analysis indicate that budesonide (using preparations other than Entocort EC) and conventional corticosteroids (e.g., prednisolone) were associated with similar remission rates in patients with mildly to moderately active Crohn's disease (CDAI scores of 200-300), although conventional corticosteroids were more likely to induce remission than oral budesonide when the patient population included individuals with severely active Crohn's disease.

Safety and efficacy of oral budesonide delayed-release capsules for maintenance therapy of Crohn's disease has been established in 4 randomized, double-blind, placebo-controlled studies of 12 months' duration in patients 18-73 (mean: 37) years of age, 60% of whom were female and 99% of whom were Caucasian. The mean CDAI score at study entry was 96 and approximately 75% had exclusively ileal disease. Budesonide has been effective in prolonging time to relapse defined as an increase in CDAI score of at least 60 units to a total score exceeding 150 or withdrawal secondary to disease deterioration. The median time to relapse in pooled analysis was 268 or 154 days for budesonide (6 mg daily) or placebo, respectively, and budesonide reduced the portion of patients with loss of symptom control relative to placebo at 3 months (28 versus 45%, respectively).

The potential benefits of corticosteroids for maintenance therapy of Crohn's disease should be considered carefully, because both conventional corticosteroids and budesonide do not prevent relapses and the drugs (especially conventional corticosteroids) may produce severe adverse reactions with long-term administration.

Crohn's Disease in Pediatric Patients

Although safety and efficacy of budesonide delayed-release capsules in pediatric patients have not been established, budesonide (using preparations other than Entecort EC) has been used for the management of mildly to moderately active Crohn's disease in a limited number of children 9.5-18 years of age. In one retrospective study in pediatric patients 9.5-18 years of age with mild to moderately active Crohn's disease (Pediatric Crohn's Disease Activity Index [PCDI] score of 12.5-40), budesonide pH-dependent-release preparations (0.45 mg/kg daily up to a maximum dosage of 9 mg daily) were compared with prednisone (2 mg/kg daily up to a maximum dosage of 40 mg daily). Remission was defined as the absence of clinical symptoms and a PCDI score of 10 or less, assessed after 8 weeks of treatment. Results of this study showed that 48 or 77% of pediatric patients achieved remission with budesonide or prednisone, respectively. In addition, 59% of pediatric patients who had shown no improvement with previous mesalamine therapy achieved remission with budesonide.

In addition, results of a 12-week comparator-drug (prednisone versus budesonide) controlled study in pediatric patients 8-18 years of age (weighing more than 20 kg) with mildly to moderately active Crohn's disease (Pediatric Crohn's Disease Activity Index [PCDI] score of 12.5-40), indicate that remission rates in children receiving prednisone (40 mg daily for 2 weeks and then tapered to discontinuance) were similar (50% for prednisone versus 47% for budesonide) to those receiving budesonide pH- dependent-release preparations (9 mg daily for 8 weeks and then tapered to discontinuance). Total incidence of adverse effects was substantially lower (about 32% for budesonide versus 71% for prednisone) and less severe in pediatric patients receiving budesonide than those receiving prednisone.

For further information on the management of Crohn's disease,

Asthma

Budesonide powder is used by oral inhalation, via the Turbuhaler (no longer commercially available in the US), for the treatment of bronchial asthma in adults and pediatric patients 6 years of age and older who require chronic administration of corticosteroids to control symptoms. Budesonide inhalation suspension (administered via nebulization) is used by oral inhalation for the treatment of bronchial asthma in children 1-8 years of age. The inhalation aerosol containing budesonide in fixed combination with formoterol fumarate (Symbicort) is used by oral inhalation for the treatment of asthma in adults and adolescents 12 years of age and older. The fixed combination of budesonide and formoterol fumarate is used only in patients with asthma who have not responded adequately to long-term asthma controller therapy, such as inhaled corticosteroids, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β2-adrenergic agonist. Once asthma control is achieved and maintained, the patient should be assessed at regular intervals and therapy should be stepped down (e.g., discontinuance of budesonide in fixed combination with formoterol fumarate), if possible without loss of asthma control, and the patient should be maintained on long-term asthma controller therapy, such as inhaled corticosteroids. Budesonide in fixed combination with formoterol fumarate should not be used in patients whose asthma is adequately controlled on low or medium dosage of inhaled corticosteroids.(See Asthma-related Death under Warnings/Precautions: Warnings, in Cautions.) Orally inhaled budesonide, alone or in fixed combination with formoterol fumarate, should not be used in the management of acute bronchospasm.

Well-controlled clinical studies have shown that oral inhalation of budesonide improves pulmonary function and relieves symptoms of bronchial asthma. Following continuous use of the oral inhalation of budesonide powder (administered via a Turbuhaler) or the micronized suspension (administered via nebulization), improvement may occur within 1 or 2-8 days of therapy, respectively; however, maximum symptomatic relief may require at least 1-2 or 4-6 weeks, respectively. In corticosteroid-dependent patients, use of budesonide oral inhalation therapy may permit a reduction in the daily maintenance dosage of the systemic corticosteroid and gradual discontinuance of corticosteroid maintenance dosages. In 2 randomized, double-blind, placebo-controlled clinical studies in patients with mild to severe asthma, orally inhaled budesonide (160 or 320 mcg twice daily) in fixed combination with formoterol fumarate (9 mcg twice daily) produced greater improvement in most indices of pulmonary function (e.g., mean percent change from baseline in forced expiratory volume in 1 second [FEV1] or morning and evening peak expiratory flow rate [PEFR]) than either drug alone and similar efficacy as concurrent therapy with both agents given separately. For information on the stepped-care approach to drug therapy in asthma,

Chronic Obstructive Pulmonary Disease

The inhalation aerosol containing budesonide in fixed combination with formoterol fumarate is used by oral inhalation for maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Orally inhaled budesonide in fixed combination with formoterol fumarate is not indicated for the relief of acute bronchospasm.

In 2 randomized, double-blind, placebo-controlled studies of 6 or 12 months' duration in patients with COPD, orally inhaled budesonide (320 mcg twice daily) in fixed combination with formoterol fumarate (9 mcg twice daily) produced greater improvements in the mean percent change from baseline in predose FEV1 than formoterol alone or placebo and in 1-hour postdose FEV1 than budesonide alone or placebo. The fixed combination containing 160 mcg of budesonide and 9 mcg of formoterol fumarate twice daily did not produce greater improvements from baseline in predose FEV1 than formoterol alone or placebo. Therefore, the fixed combination containing 320 mcg of budesonide and 9 mcg of formoterol fumarate twice daily is the only recommended dosage for the treatment of airflow obstruction in COPD. For information on the stepped-care approach to drug therapy in COPD,

Dosage and Administration

Administration

Budesonide is administered orally as delayed-release capsules. For oral inhalation, budesonide is available as a micronized suspension administered via nebulization and as an inhalation aerosol containing budesonide in fixed combination with formoterol fumarate (Symbicort) administered via an oral aerosol inhaler with hydrofluoroalkane (HFA) propellant. Patients receiving orally inhaled budesonide should rinse their mouth with water after each dose to remove residual drug in the oropharyngeal area and to minimize the development of fungal overgrowth and/or infection.

Oral Administration

Budesonide is administered orally once daily as delayed-release capsules containing enteric-coated granules. The capsules should be swallowed intact; they should not be chewed or broken. However, limited data indicate that the release characteristics of the delayed-release capsules were not affected when the unencapsulated granules were added to applesauce for 30 minutes. Because grapefruit juice has been shown to inhibit cytochrome P-450 (CYP) isoenzyme 3A4, an enzyme involved in the metabolism of budesonide, concomitant use of budesonide capsules with grapefruit juice should be avoided.(See Drug Interactions: Drugs or Foods Affecting Hepatic Microsomal Enzymes.) Although administration with a high-fat meal delays time to reach peak plasma concentrations of budesonide by about 2.5 hours, the manufacturer makes no specific recommendation regarding administration of budesonide capsules with food.

Oral Inhalation via Nebulization

Commercially available budesonide suspension for oral inhalation is administered via nebulization.The oral inhalation suspension should not be administered parenterally or used with ultrasonic nebulizers. Budesonide inhalation suspension should be administered using a jet nebulizer (with face mask or mouthpiece) connected to a compressor that has an adequate air flow. The face mask should be properly adjusted to optimize delivery and to avoid exposure of the eyes to nebulized drug. When a face mask is used for nebulization of budesonide suspension, the face should be washed after each use to avoid dermatologic corticosteroid effects (e.g., rash, contact dermatitis). In clinical trials, a Pari-LC-Jet Plus Nebulizer was used to deliver budesonide inhalation suspension (Pulmicort Respules). The manufacturer states that safety and efficacy of budesonide inhalation suspension administered by a nebulizer other than the Pari-LC-Jet Plus Nebulizer or a compressor other than the Pari Master compressor have not been established. Since stability and safety of budesonide suspension mixed with other drugs in a nebulizer have not been established, budesonide oral inhalation suspension for nebulization should not be mixed with other drugs. When the commercially available Pulmicort Respules are used, the amount of drug delivered to the lungs depends on the type of jet nebulizers used, performance of the compressor, and on factors such the patient's inspiratory flow. Using standardized in vitro testing at a flow rate of 5.5 L per minute, the mean delivered dose at the mouthpiece of the commercially available budesonide suspension (Pulmicort Respules) is 17% of the nominal dose.

Oral Inhalation via Aerosol Inhaler

Budesonide in fixed combination with formoterol fumarate (Symbicort) is administered by oral inhalation using an oral aerosol inhaler with hydrofluoroalkane (HFA) propellant. Budesonide/formoterol fumarate inhalation aerosol should only be used with the actuator supplied with the product. Before each inhalation, the inhaler must be shaken well for 5 seconds. The aerosol inhaler should be test sprayed twice into the air (away from the face) before initial use, and shaken well for 5 seconds before each spray. If the inhaler has not been used for more than 7 days or if the inhaler was dropped, the inhaler should be test sprayed twice into the air (away from the face) and shaken well for 5 seconds before each spray. Rinsing the mouth after inhalation of budesonide/formoterol fumarate inhalation aerosol and spitting out the water are advised. The mouthpiece of the inhaler should be wiped clean with a dry cloth every 7 days. The inhaler should be discarded when the labeled number of inhalations have been used or within 3 months after removal from the foil pouch. The canister should never be immersed in water to determine the amount of drug remaining in the canister (''float test'').

Each actuation of the oral aerosol inhaler containing the fixed combination of budesonide and formoterol fumarate delivers 91 or 181 mcg of budesonide and 5.1 mcg of formoterol fumarate from the valve. Dosages of budesonide and formoterol fumarate in the fixed-combination inhalation aerosol are expressed in terms of drug delivered from the mouthpiece; each actuation of the inhaler delivers 80 or 160 mcg of budesonide and 4.5 mcg of formoterol fumarate from the actuator per metered spray. The amount of drug delivered to the lungs depends on factors such as the patient's coordination between the actuation of the inhaler and inspiration through the delivery system. The commercially available inhalation aerosol containing budesonide in fixed combination with formoterol fumarate delivers 60 metered sprays per 6- or 6.9-g canister and 120 metered sprays per 10.2-g canister.

Dosage

Crohn's Disease

For the management of mild to moderately active Crohn's disease involving the ileum and/or the ascending colon, the recommended adult oral dosage of delayed-release budesonide capsules is 9 mg administered daily in the morning for 8 weeks. Results of a double-blind, multicenter study indicate that in patients who have not experienced remission during the initial 8-week course of budesonide, a second 8-week (16 weeks of continuous therapy) course with the drug may be beneficial in some patients. The manufacturer states that for recurrent episodes of active Crohn's disease, a repeated 8-week course of oral budesonide may be given.

For maintenance of clinical remission following 8 weeks of active treatment once symptoms have been controlled (CDAI score of less than 150), the recommended adult oral dosage of delayed-release budesonide capsules is 6 mg once daily for up to 3 months. If symptom control is maintained at 3 months, an attempt to taper dosage to complete cessation is recommended. The manufacturer states that continued therapy beyond 3 months has not been shown to provide substantial clinical benefit.

Reduction of budesonide dosage should be considered in patients receiving a known inhibitor of the CYP3A4 isoenzyme concomitantly.(See Drugs and Foods that Inhibit CYP3A4 under Drug Interactions: Drugs or Foods Affecting Hepatic Microsomal Enzymes.)

No episodes of adrenal insufficiency have been reported in patients with mild to moderately active Crohn's disease (involving the ileum and/or the ascending colon) who have been switched from oral prednisolone to oral budesonide therapy. It should be considered, however, that abrupt discontinuance of prednisolone is not recommended and, therefore, dosage of prednisolone should be tapered when initiating budesonide therapy.(See Withdrawal of Systemic Corticosteroid Therapy under Warnings/Precautions: Warnings, in Cautions.)

Asthma

The recommended initial and maximum dosages of budesonide for oral inhalation are based on previous asthma therapy. The recommended initial dosage of the oral inhalation aerosol containing budesonide in fixed combination with formoterol fumarate is based on the patient's asthma severity. Safety and efficacy of dosages exceeding those recommended by the manufacturer have not been established. The manufacturer suggests that in patients who were receiving prior oral corticosteroid therapy, reduction of alternate-day or daily dosing should be initiated approximately 1 week after starting budesonide oral inhalation, followed by further reductions after an interval of 1 or 2 weeks; decrements usually should not exceed 2.5 mg or 25% of prednisone (or its equivalent) in patients receiving budesonide powder for inhalation or inhalation suspension administered via nebulization, respectively. The manufacturer of the oral inhalation aerosol containing budesonide in fixed combination with formoterol fumarate states that patients requiring oral corticosteroids should be withdrawn slowly from systemic corticosteroid use after transferring to budesonide in fixed combination with formoterol fumarate. The manufacturer also states that prednisone dosage reduction may be accomplished by reducing the daily dosage by 2.5 mg on a weekly basis during therapy with the oral inhalation aerosol containing budesonide in fixed combination with formoterol fumarate. Once oral corticosteroids are discontinued and symptoms of asthma have been controlled, the dosage of budesonide should be titrated to the lowest effective level.(See Withdrawal of Systemic Corticosteroid Therapy under Warnings/Precautions: Warnings, in Cautions and also see Advice to Patients.)

Oral Inhalation via Nebulization in Children (1-8 years of age)

When budesonide suspension is administered via a nebulizer in children who previously were receiving bronchodilators alone, the recommended initial dosage of budesonide is 0.5 mg, given in 1 or 2 divided daily doses; the recommended maximum dosage is 0.5 mg daily. In children who were previously receiving inhaled corticosteroids, the recommended initial dosage of budesonide suspension, given via a nebulizer, is 0.5 mg, given in 1 or 2 divided daily doses; the recommended maximum dosage is 1 mg daily. In children who previously were receiving oral corticosteroids, the recommended initial dosage of budesonide inhalation suspension, given via a nebulizer, is 1 mg, given in 1 or 2 divided daily doses; the recommended maximum dosage is 1 mg daily. In children who are not receiving oral corticosteroids and who do not respond adequately to the initial once-daily administration of budesonide suspension, increasing the dosage or giving the drug in 2 divided doses daily should be considered.

In children with asthma symptoms who do not respond to nonsteroidal (e.g., bronchodilator, mast-cell stabilizer) therapy, an initial 0. 25-mg daily dosage of budesonide inhalation suspension, given via a nebulizer, may be considered. However, if the once-daily dosage does not provide adequate control of asthma symptoms, the total daily dosage should be increased and/or administered in divided doses.

Budesonide/Formoterol Fumarate Fixed-combination Therapy

In asthmatic adults and adolescents 12 years of age or older, the recommended initial dosage of the oral inhalation aerosol containing budesonide in fixed combination with formoterol fumarate is based on the patient's asthma severity. The dosage of the inhalation aerosol fixed-combination preparation is 160 or 320 mcg of budesonide and 9 mcg of formoterol fumarate (2 inhalations) twice daily, given approximately 12 hours apart (morning and evening). The maximum recommended dosage of budesonide in fixed combination with formoterol fumarate is 320 mcg of budesonide with 9 mcg of formoterol fumarate (2 inhalations) twice daily. The manufacturer states that administration of the inhalation aerosol containing budesonide in fixed combination with formoterol fumarate more frequently than twice daily or in excess of 2 inhalations twice daily is not recommended. Patients receiving the fixed combination of budesonide and formoterol fumarate should not use additional long-acting β2-agonists for any reason.

Improvement in asthma control following inhalation of budesonide in fixed combination with formoterol fumarate may occur within 15 minutes of initiating treatment, although maximum benefit may not be achieved for 2 weeks or longer after therapy initiation. Individual patients will experience a variable time to onset and degree of symptom relief. If control of asthma is inadequate after 1-2 weeks of therapy at the lower dosage, increasing the strength of the fixed combination (higher strengths contain higher dosages of budesonide only) may provide additional asthma control. If acute asthmatic symptoms arise despite therapy with budesonide in fixed combination with formoterol fumarate, a short-acting inhaled β2-adrenergic agonist should be administered for immediate relief. Patients should be advised not to discontinue budesonide in fixed combination with formoterol fumarate without medical supervision, as symptoms may recur after treatment discontinuance. If a previously effective dosage of budesonide in fixed combination with formoterol fumarate fails to provide adequate asthma control, the therapeutic regimen should be reevaluated and additional therapeutic options should be considered (e.g., increasing the strength of the fixed combination [higher strengths contain higher dosages of budesonide only], adding additional inhaled corticosteroids, initiating systemic corticosteroids). The manufacturer warns that therapy with the fixed combination of budesonide and formoterol fumarate should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma.

Chronic Obstructive Pulmonary Disease

Budesonide/Formoterol Fumarate Fixed-combination Therapy

For maintenance therapy of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), the recommended dosage of the oral inhalation aerosol containing budesonide in fixed combination with formoterol fumarate in adults is 320 mcg of budesonide and 9 mcg of formoterol fumarate (2 inhalations) twice daily (morning and evening). In clinical studies, the fixed combination containing 160 mcg of budesonide and 9 mcg of formoterol fumarate (2 inhalations) twice daily did not produce greater improvements from baseline in predose FEV1 than formoterol alone or placebo; therefore, the fixed combination containing 320 mcg of budesonide and 9 mcg of formoterol fumarate (2 inhalations) twice daily is the only recommended dosage for the treatment of airflow obstruction in COPD. If shortness of breath occurs despite therapy with budesonide in fixed combination with formoterol fumarate, a short-acting inhaled β2-adrenergic agonist should be taken for immediate relief. Patients should be advised not to discontinue budesonide in fixed combination with formoterol fumarate without medical supervision, as symptoms may recur after treatment discontinuance. The manufacturer warns that therapy with the fixed combination of budesonide and formoterol fumarate should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. The manufacturer states that administration of the inhalation aerosol containing budesonide in fixed combination with formoterol fumarate more frequently than twice daily or in excess of 2 inhalations twice daily is not recommended. Patients receiving the fixed combination of budesonide and formoterol fumarate should not use additional long-acting β2-agonists for any reason.

Special Populations

Patients with Crohn's disease and moderate to severe hepatic impairment should be monitored for increased signs and symptoms of hypercorticism; reduction of budesonide oral dosage is recommended in these patients.

When budesonide is used in fixed combination with formoterol fumarate, dosage requirements for formoterol fumarate should be considered.

The manufacturer of budesonide in fixed combination with formoterol fumarate states that dosage adjustment is not required in geriatric patients. The manufacturer of budesonide in fixed combination with formoterol fumarate makes no specific dosage recommendations for patients with hepatic or renal impairment at this time. However, since budesonide and formoterol fumarate are cleared predominantly by the liver, impaired liver function theoretically may lead to accumulation of the drugs in plasma. Therefore, the manufacturer of budesonide in fixed combination with formoterol fumarate states that patients with hepatic disease should be closely monitored.

Cautions

Contraindications

Known hypersensitivity to budesonide or any ingredient in the formulation.

Orally inhaled budesonide is contraindicated as primary treatment of acute asthmatic attacks or status asthmaticus when intensive measures (e.g., an orally inhaled β2adrenergic agonist, an orally inhaled anticholinergic agent, subcutaneous epinephrine, IV aminophylline, and/or an oral/IV glucocorticoid) are required.

Budesonide in fixed combination with formoterol fumarate (Symbicort) is contraindicated as primary treatment of status asthmaticus or other acute episodes of asthma or chronic obstructive pulmonary disease (COPD) when intensive measures are required.

When budesonide is used in fixed combination with formoterol fumarate, contraindications associated with formoterol fumarate should be considered.

Warnings/Precautions

Warnings

Use of Fixed Combinations

When budesonide is used in fixed combination with formoterol fumarate, the usual cautions, precautions, contraindications, and interactions associated with formoterol fumarate should be considered. Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug in the fixed combination.

Asthma-related Death

Long-acting β2-adrenergic agonists, such as formoterol, a component of Symbicort, increase the risk of asthma-related death. Data from a large (approximately 26,000 patients), placebo-controlled study (Salmeterol Multi-center Asthma Research Trial [SMART]) evaluating the safety of another long-acting β2-adrenergic agonist, salmeterol, in patients with asthma showed an increase in asthma-related deaths in patients receiving salmeterol. In addition, available data from controlled clinical trials suggest that long-acting β2-adrenergic agonists increase the risk of asthma-related hospitalization in pediatric and adolescent patients.

Therefore, in the treatment of asthma, the fixed combination of budesonide and formoterol fumarate is used only in patients who have not responded adequately to long-term asthma controller therapy, such as inhaled corticosteroids, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β2-adrenergic agonist.(See Uses: Asthma.)

Withdrawal of Systemic Corticosteroid Therapy

In patients being switched from systemic corticosteroids to oral or orally inhaled budesonide, systemic corticosteroid therapy should be withdrawn gradually because life-threatening adrenal insufficiency may occur. Patients who have been maintained on 20 mg or more of prednisone (or its equivalent) daily may be most susceptible to such adverse events, particularly when their systemic corticosteroid therapy has been almost completely withdrawn.In most patients, following withdrawal of systemic corticosteroid therapy, several months are required for total recovery of HPA function. These patients should be carefully monitored during and for a number of months after withdrawal of systemic corticosteroids because of the risk of corticosteroid withdrawal symptoms (e.g., joint pain, muscular pain, lassitude, depression); acute adrenal insufficiency during exposure to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with acute electrolyte loss; or symptomatic exacerbation of allergic conditions previously controlled by systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Clinicians should be alert for the potential for eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and/or neuropathy consistent with Churg-Strauss syndrome. In asthmatic patients, death, possibly resulting from acute adrenal insufficiency, has occurred rarely during and after transfer from a systemic corticosteroid to budesonide oral inhalation therapy. Systemic corticosteroid dosage should be carefully tapered and patients should be monitored during dosage reduction for objective signs of adrenal insufficiency and for benign intracranial hypertension. In general, the greater the dosage and duration of systemic corticosteroid therapy, the greater the time required for withdrawal of systemic corticosteroids and replacement by orally inhaled corticosteroids.

Immunosuppressed Patients

Patients who are taking immunosuppressant drugs have increased susceptibility to infections compared with healthy individuals, and certain infections (e.g., varicella [chickenpox], measles) can have a more serious or even fatal outcome in such patients, particularly in children. In patients who have not had these diseases or been properly vaccinated, particular care should be taken to avoid exposure. If exposure to varicella occurs in such individuals, administration of varicella zoster immune globulin (VZIG) or pooled IV immunoglobulin (IVIG) may be indicated; if exposure to measles occurs, pooled IM immune globulin (IG) may be indicated. If varicella (chickenpox) develops, treatment with an antiviral agent may be considered. It is not known how the dosage, route and duration of administration of a corticosteroid, or the contribution of the underlying disease and/or prior corticosteroid therapy affect the risk of developing a disseminated infection.For additional information,

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression

Since glucocorticoids can reduce HPA-axis response to stress (e.g., surgery), supplementation with a systemic corticosteroid in patients undergoing such stress is recommended.

Bronchospasm

As with other inhaled drugs for asthma, bronchospasm may occur, resulting in an immediate increase in wheezing following oral inhalation of budesonide. If bronchospasm occurs, appropriate treatment (e.g., use of a short-acting β-adrenergic agonist) should be initiated immediately, and budesonide therapy should be discontinued and alternate therapy instituted.

General Precautions

Infections

Localized candidal infections of the mouth and/or pharynx have been reported in patients receiving orally inhaled budesonide therapy. When infection occurs, appropriate local or systemic antifungal treatment may be necessary while still continuing with inhaled budesonide therapy, although discontinuance of such therapy (under close medical supervision) may be required in some patients. Inhaled corticosteroid therapy should be used with extreme caution, if at all, in patients with clinical or asymptomatic Mycobacterium tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. Clinicians should remain vigilant for the possible development of pneumonia in patients with COPD who are receiving budesonide in fixed combination with formoterol fumarate, since the clinical features of pneumonia and COPD exacerbations frequently overlap. Lower respiratory tract infections, including pneumonia, have been reported in patients with COPD following the administration of inhaled corticosteroids.

Ophthalmic Effects

Glaucoma, increased intraocular pressure (IOP), and cataracts have been reported rarely in patients receiving orally inhaled corticosteroids.

Concomitant Disease States

The manufacturer states that budesonide delayed-release capsules should be used with caution in patients with tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, a family history of diabetes or glaucoma, or any other condition in which glucocorticoids may be associated with adverse effects.

Systemic Corticosteroid Effects

Administration of higher than recommended dosages of orally inhaled budesonide or prolonged oral administration of budesonide capsules may result in manifestations of hypercorticism and suppression of HPA function.

Long-Term Administration

The long-term local and systemic effects of budesonide in humans, particularly local effects on developmental or immunologic processes in the mouth, pharynx, trachea, and lung, are unknown.

Musculoskeletal Effects

Long-term use of orally inhaled corticosteroids may affect normal bone metabolism, resulting in a loss of bone mineral density. The manufacturer of budesonide in fixed combination with formoterol states that patients with major risk factors for decreased bone mineral density, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated using established standards of care. Since patients with COPD often have multiple risk factors for reduced bone mineral density, assessment of bone mineral density is recommended prior to initiation of therapy with budesonide in fixed combination with formoterol fumarate and periodically thereafter. If appreciable reductions in bone mineral density are seen and use of budesonide in fixed combination with formoterol fumarate is considered to be important for the patient's COPD therapy, use of agents to treat or prevent osteoporosis should be strongly considered.

Specific Populations

Pregnancy

Category B (orally inhaled powder and inhalation suspension); category C (oral capsules and the fixed combination of budesonide and formoterol fumarate oral inhalation aerosol). Hypoadrenalism may occur in infants of women receiving corticosteroid therapy during pregnancy. These infants should be carefully monitored.

Lactation

It is not known whether budesonide is distributed into milk; however, other corticosteroids are distributed into milk. Because of the potential for serious adverse reactions from corticosteroids in nursing infants, a decision should be made whether to discontinue nursing or budesonide, taking into account the importance of the drug to the woman. The extent of distribution of budesonide into milk has not been determined. The manufacturer of budesonide in fixed combination with formoterol fumarate (Symbicort) inhalation aerosol states that since no data from controlled trials are available on the use of this preparation in nursing women, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy of oral budesonide delayed-release capsules have not been established in pediatric patients younger than 18 years of age with Crohn's disease. Oral budesonide (using preparations other than Entecort EC) has been used for the management of mild to moderately active Crohn's disease in a limited number of pediatric patients without unusual adverse effects. Benign intracranial hypertension has been reported in at least one pediatric patient with Crohn's disease receiving the drug.

Safety and efficacy of budesonide inhalation suspension or powder have not been established in children younger than 6 years of age. Efficacy of budesonide inhalation suspension has not been established in children younger than 1 year of age, while safety of the suspension has not been established in children younger than 6 months of age. Safety and efficacy of budesonide in fixed combination with formoterol fumarate (Symbicort) inhalation aerosol in patients 12 years of age or older with asthma have been established in studies of up to 12 months' duration; however, the manufacturer states that safety and efficacy of the fixed combination preparation in children 6 to younger than 12 years of age with asthma have not been established. Use of corticosteroids may lead to suppression of growth in children and adolescents. Therefore, children receiving prolonged therapy with orally inhaled budesonide should be monitored periodically for possible adverse effects on growth and development.

Geriatric Use

Clinical studies of oral budesonide delayed-release capsules did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. While other clinical experience with budesonide inhalation powder or inhalation suspension or with the inhalation aerosol containing budesonide in fixed combination with formoterol fumarate has not revealed age-related differences in response, oral drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. No substantial differences in safety and efficacy of budesonide in fixed combination with formoterol fumarate were observed in geriatric patients relative to younger adults. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.(See Dosage and Administration: Special Populations.)

Hepatic Impairment

May affect elimination of corticosteroids; increased systemic availability of oral budesonide capsules has been reported in patients with liver cirrhosis. Patients with mild hepatic impairment are minimally affected. Pharmacokinetics were not studied in patients with severe hepatic impairment. The manufacturer states that patients with hepatic disease receiving budesonide in fixed combination with formoterol fumarate should be closely monitored.(See Dosage and Administration: Special Populations.)

Renal Impairment

Pharmacokinetics of budesonide have not been studied in patients with renal impairment. However, since only the metabolites (having negligible glucocorticoid activity), and not the unchanged drug, are excreted by the kidneys, increased adverse effects are not expected in such patients receiving the drug.

Common Adverse Effects

Adverse effects occurring in at least 5% of patients receiving budesonide oral capsules include headache, dizziness, nausea, vomiting, dyspepsia, diarrhea, abdominal pain, flatulence, sinusitis, respiratory infection, viral infection, pain (including back pain), arthralgia, and fatigue. Adverse effect profile in long-term treatment was similar to that of short-term treatment.

Adverse effects occurring in 1% or more of patients receiving budesonide by oral inhalation (as a powder using a Turbuhaler [no longer commercially available in the US] or as an inhalation suspension, administered via nebulization) include infections (e.g., respiratory infection, ocular infection), pharyngitis, rhinitis, sinusitis, viral infection (e.g., herpes simplex), cough, voice alteration, stridor, earache, otitis (media or externa), viral infection, flu-like syndrome, moniliasis, oral candidiasis, flu syndrome, fever, headache, migraine, insomnia, dysphonia, hyperkinesia, asthenia, fatigue, emotional lability, pain (e.g., back pain), arthralgia, myalgia, hypertonia, fractures, dyspepsia, gastroenteritis, nausea, vomiting, diarrhea, abdominal pain, dry mouth, taste perversion, weight gain, anorexia, epistaxis, ecchymosis, purpura, cervical lymphadenopathy, conjunctivitis, rash (may be pustular), pruritus, allergic reaction, contact dermatitis, syncope, and chest pain.

Drug Interactions

The following information addresses potential interactions with budesonide. When budesonide is used in fixed combination with formoterol fumarate, interactions associated with formoterol fumarate should be considered. No formal drug interaction studies have been performed to date with the fixed-combination preparation containing budesonide and formoterol fumarate.

Drugs or Foods Affecting Hepatic Microsomal Enzymes

Drugs and Foods that Inhibit Isoenzyme CYP3A4

Since budesonide is metabolized in the liver by the cytochrome P-450 (CYP) 3A4 isoenzyme, concomitant use with drugs that are potent inhibitors of the CYP3A4 isoenzyme may result in increased plasma budesonide concentrations. Concomitant use of oral budesonide with oral ketoconazole resulted in an eightfold increase in budesonide systemic exposure. Patients in whom concomitant use of a known inhibitor of the CYP3A4 isoenzyme (e.g., erythromycin, itraconazole, clarithromycin, ketoconazole, indinavir, ritonavir, saquinavir) with oral budesonide capsules is indicated should be carefully monitored for increased signs and symptoms of hypercorticism and reduction of budesonide dosage should be considered.

Oral contraceptives containing ethinyl estradiol (also metabolized by CYP3A4 isoenzyme) do not appear to affect the pharmacokinetics of budesonide; in addition, budesonide does not appear to affect plasma concentrations of these oral contraceptives.

Concomitant use of oral budesonide delayed-release capsules with grapefruit juice resulted in a twofold increase in budesonide systemic exposure; therefore, such concomitant use should be avoided.

Drugs that Induce Isoenzyme CYP3A4

Concomitant administration of budesonide with drugs that induce CYP3A4 isoenzyme may result in decreased budesonide plasma concentrations.

Drugs Affecting GI pH

Because budesonide delayed-release oral capsules containing enteric-coated granules are formulated to dissolve at a relatively nonacidic pH (exceeding 5.5)(see Description), concomitant use of drugs that affect GI pH may affect release properties and systemic uptake of oral budesonide delayed-release capsules. Although administration of gastric antisecretory agents (e.g., omeprazole, cimetidine) did not appear to affect the pharmacokinetic parameters (e.g., absorption) of the commercially available budesonide delayed-release capsules, slightly increased peak plasma concentrations and rate of absorption of budesonide have been reported following concomitant use of cimetidine (1 g daily) with a nonenteric-coated formulation of budesonide, resulting in substantial suppression of the hypothalamic-pituitary-adrenal (HPA) axis.

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